Agglomerated hydrophilic complexes with multi-phasic release characteristics

ABSTRACT

The present invention relates to a controlled release formulation which includes a therapeutically active medicament, a heterodisperse gum matrix, a pharmaceutically acceptable diluent, and an effective amount of a pharmaceutically acceptable surfactant and/or wetting agent to provide a multi-phasic controlled release of a therapeutically active medicament. The invention also relates to a method of preparing the same.

BACKGROUND OF THE INVENTION

The advantages of controlled release products are well known in thepharmaceutical field and include the ability to maintain a desired bloodlevel of a medicament over a comparatively longer period of time whileincreasing patient compliance by reducing the number of administrationsnecessary to achieve the same. These advantages have been attained by awide variety of methods. For example, different hydrogels have beendescribed for use in controlled release medicines, some of which aresynthetic, but most of which are semi-synthetic or of natural origin. Afew contain both synthetic and non-synthetic material. However, some ofthe systems require special process and production equipment, and inaddition some of these systems are susceptible to variable drug release.

Oral controlled release delivery systems should ideally be adaptable sothat release rates and profiles can be matched to physiological andchronotherapeutic requirements.

For the most part, the release rate of oral delivery systems have beenclassified according to the mechanism of release, such as zero order,first order, second order, pseudo-first order, and the like, althoughmany pharmaceutical compounds release medicament via other, complicatedmechanisms.

First order mechanisms refer to situations where the reaction rate isdependent on the concentration of the reacting substance (and thereforeis dependent on the first power of the reactant). In such mechanisms,the substance decomposes directly into one or more products.

Second order mechanisms occur when the experimentally determined rate ofreaction is proportional to the concentration of each of two reactants,or to the second power of the concentration of one reactant.

Pseudo first order reactions are generally defined as second orderreactions which behave as though they are governed by a first ordermechanism, and occur, for example, when the amount of one reactingmaterial is manipulated by being present in great excess or beingmaintained at a constant concentration as compared to the othersubstance. In such circumstances, the reaction rate is determined by themanipulated substance.

Zero order mechanisms refer to situations where the reaction rate isindependent of the concentration of the reacting substance (andtherefore is dependent on the zero power of the reactant), the limitingfactor being something other than the concentration of the reactingsubstance (e.g., the medicament). The limiting factor in a zero ordermechanism may be, for example, the solubility of the reacting substanceor the light intensity in photochemical reactions.

As previously mentioned, however, many chemical reactions are not simplereactions of zero-, first-, or second-order, and the like, and insteadcomprise a combination of two or more reactions.

Moreover, other factors may influence the reaction rate, includingtemperature, pH, food effect variability, ions and ionic strengthdependency, viscosity dependency, corrosion/erosion variability, contentuniformity problems, flow and weight uniformity problems, carryingcapacity and mechanical strength problems, hydrolysis, photochemicaldecomposition, interaction between components (such as interactionsbetween the drug and other ingredients in the formulation, such asbuffers, preservatives, and the like), the concentration of solvents oflow dielectric constant (when the reaction involves oppositely chargedions), etc.

Generally, controlled release pharmaceutical formulations which providezero order release characteristics have been considered most desirablebecause such a mechanism would theoretically provide constant druglevels. This is based on the assumption that the rate of elimination isdeterminative of the release rate of the medicament from theformulation, rather than the rate of absorption, and the like.

However, for medicaments which are not very soluble in the stomach andwhere absorption is desired for a prolonged period of time, a bimodalrelease mechanism is considered to be desirable.

Bimodal or multi-phasic release is characterized by an initial high ratefollowed by a slower rate as the dosage form passes the upper portion ofthe small intestine where absorption is maximum and finally anotherhigher rate as the dosage form passes into the further end of theintestine where absorption is less than before.

Bimodal release is considered to be advantageous for a number ofreasons, including but not limited to the fact that bimodal releaseallows the formulator to compensate for changing absorption rates of themedicament in the gastrointestinal tract by providing a rapid onset ofaction (when the formulation is located in the stomach) and compensatefor relatively slow absorption by providing a relatively rapid releaserate (e.g., when the formulation is located in the large intestine).

Bimodal release formulations have been provided in a number of differentmanners to date.

For example, International Publication Number WO/87/00044 describestherapeutic formulations which are said to have bimodal releasecharacteristics. WO 87/00044 describes a carrier base material fortherapeutically active medicaments in a solid dosage formulation thatare said to produce a bimodal controlled release profile characterizedby a rapid initial release of medicament followed by a substantiallyconstant rate of release for a period of time, after which the releaserate is greater than the constant rate previously observed. The carrierbased material comprises bimodal hydroxypropylmethylcellulose etherswith a methoxy content of 19-30%, a hydroxy propoxy content of 4-12%, aviscosity of 40-19,000 cps, an average molecular weight of20,000-140,000, and which demonstrates a bimodal release profile inaccordance with an assay method described therein. The bimodalhydroxypropylmethylcelluloses comprise 5-99% by weight of the totalformulation, depending upon the active ingredient and length of drugreleased desire.

A. C. Shah et al., "Gel-Matrix Systems Exhibiting Bimodal ControlledRelease For Oral Drug Delivery", Journal of Controlled Release, 9(1989),pp. 169-175, further reported that certain "types" ofhydroxypropylmethylcellulose ethers are found to display a bimodal drugrelease profile. However, in that study, series ofhydroxypropylmethylcellulose ether polymers were found to providebimodal and non-bimodal release profiles from polymer-drug matrixtablets, which results appeared to depend upon the supplier of thepolymer (and therefore upon, e.g., the method of manufacture, ioniccomposition, variations in the distribution of substituent groups, ordistribution of molecular weight fractions).

P. Giunchedi et al., "Ketoprofen Pulsatile Absorption From `MultipleUnit` Hydrophilic Matrices" International Journal of Pharmaceutics,77(1991), pp. 177-181 described an extended release oral formulation ofKetoprofen comprising a multiple unit formulation constituted by fourhydrophilic matrices of identical composition, each containing 50 mg ofdrug and prepared with hydroxypropylmethylcellulose (Methocel®) andplaced in a gelatin capsule. Pulsatile plasma levels (2 peaks at 2nd and8th hours after dosing) were said to be obtained, whereas in vitro testsresulted in a fairly constant drug release.

U. Conte et al., "A New Ibuprofen Pulsed Release Oral Dosage Form", DrugDevelopment And Industrial Pharmacy, 15(14-16), pp 2583-2596 (1989)reported that a pulsed released pattern was obtained from a 3-layertablet wherein two layers contained a dose of drug, and an intermediatelayer acted as a control element separating the drug layers. The controlelement was a mixture of water-swellable polymers(hydroxypropylmethylcelluloses). An outer film of an impermeable polymercoated the tablet. A superdisintegrant (sodium starch glycolate andcross-linked polyvinyl pyrrolidone) was included in the drug layers.

K. A. Kahn et al, "Pharmaceutical Aspects And In-Vivo Performance OfBrufen Retard--An Ibuprofen SR Matrix Tablet", Proced. Intern. Symp.Control. Rel. Bioact. Mater., 18(1991), Controlled Release Society,Inc., describes a formulation containing 800 mg of ibuprofen which issaid to provide a bimodal release pattern. The release retarding agentutilized therein was xanthan gum. The ingredients were blended to theappropriate xanthan gum content, and thereafter compressed into tabletsand film coated. The amount of xanthan gum included inversely affectedthe rate of drug release. An increase in drug particle size or quantityof film-coat per tablet did not significantly effect the rate of drugrelease. Although an increase in particle size of the xanthan gum causeda more pronounced burst effect, the application of the film-coatovercame this burst effect. The rapid initial release of the medicamentwas hypothesized to be related to changes in the formation of the gellayer, wherein larger particles gel more slowly and are sloughed offbefore a coherent matrix can form.

In our U.S. Pat. Nos. 4,994,276, 5,128,143, and 5,135,757, herebyincorporated by reference, we reported that a controlled releaseexcipient which is comprised of synergistic heterodispersepolysaccharides (e.g., a heteropolysaccharide such as xanthan gum incombination with a polysaccharide gum capable of cross-linking with theheteropolysaccharide, such as locust bean gum) is capable of processinginto oral solid dosage forms using either direct compression, followingaddition of drug and lubricant powder, conventional wet granulation, ora combination of the two. The release of the medicament from theformulations therein proceeded according to zero-order or first-ordermechanisms.

The controlled release excipients disclosed in U.S. Pat. Nos. 4,994,276,5,128,143, and 5,135,757 are commercially available under the tradenameTIMERx™ from Edward Mendell Co., Inc., Patterson, N.Y., which is theassignee of the present invention.

OBJECTS AND SUMMARY OF THE INVENTION

It is therefore an object of the present invention to provide aformulation capable of providing multi-phasic or bi-phasic controlledrelease of a therapeutically active medicament.

It is a further object of the present invention to provide a means ofconverting the mechanism of drug release provided by formulationscomprising the excipient described in U.S. Pat. Nos. 4,994,276,5,128,143, and 5,135,757 from zero-order or first-order to a bi-phasicor multi-phasic mechanism.

It is a further object of the present invention to provide a controlledrelease tablet which releases a therapeutically active medicamentaccording to bi- or multi-phasic kinetics.

The above-mentioned objects and others are achieved by virtue of thepresent invention, which relates in part to a controlled releaseformulation comprising a controlled release excipient comprising aheterodisperse polysaccharide component and a saccharide component; afurther component comprising a surfactant and/or a wetting agent; and atherapeutically active medicament. More particularly, it has now beensurprisingly discovered that combination of pharmaceutically acceptablesurfactants and/or wetting agents in the controlled release excipientsdisclosed in U.S. Pat. Nos. 4,994,276, 5,128,143, and 5,135,757 can beused to trigger changes in release patterns and produce bi- ormulti-phasic profiles of the final formulation, possibly via furtherchanges in cross-linking, gel strength and gel-sol transitions.

The present invention further relates to a controlled release oral soliddosage form, comprising a heterodisperse material comprising aheteropolysaccharide gum and a homopolysaccharide gum capable ofcross-linking said heteropolysaccharide gum in the presence of aqueoussolutions, the ratio of said heteropolysaccharide gum to saidhomopolysaccharide gum being from about 1:3 to about 3:1; an inertpharmaceutical diluent selected from the group consisting ofmonosaccharide, a disaccharide, a polyhydric alcohol, and mixturesthereof, the ratio of said inert diluent to said heterodisperse materialbeing from about 3:7 to about 7:3; and an effective amount of apharmaceutically acceptable surfactant or wetting agent to provide amulti-phasic release of a therapeutically active agent. In a preferredembodiment, the formulation of the present invention comprises a tablet.

The present invention further relates to a method for preparing an oralsolid dose formulation providing a multi-phasic release of atherapeutically active medicament when said dosage form is exposed toaqueous or gastric fluid. In the method, a heteropolysaccharide gum ismixed with a homopolysaccharide gum capable of cross-linking saidheteropolysaccharide gum in the presence of aqueous solutions, such thatthe ratio of said heteropolysaccharide gum to said homopolysaccharidegum is from about 1:3 to about 3:1, to obtain a heterodisperse gummatrix. An inert pharmaceutical diluent is added to said heterodispersegum matrix such that the ratio of the inert diluent to saidheterodisperse gum matrix is from about 3:7 to about 7:3. An effectiveamount of a medicament is added to render a therapeutic effect. Aneffective amount of a pharmaceutically acceptable surfactant or wettingagent is added to provide a multi-phasic release of said medicament whenthe dosage form is exposed to aqueous fluid.

BRIEF DESCRIPTION OF THE DRAWINGS

The following drawings are illustrative of embodiments of the inventionand are not meant to limit the scope of the invention as encompassed bythe claims.

FIG. 1 is a graphical representation of the dissolution curve (expressedas percent dissolved over time) provided by the tablets of Example 2 (nosurfactant);

FIGS. 2-9 are graphical representations of the dissolution curves(expressed as percent dissolved over time) provided by the tablets ofExamples 3-10 (surfactant(s) included);

FIG. 10 is a graphical representation of the dissolution curve(expressed as release rate over time) provided by the tablets of Example2 (no surfactant);

FIGS. 11-18 are graphical representations of the dissolution curves(expressed as release rate over time) provided by the tablets ofExamples 3-10 (surfactant(s) included).

DETAILED DESCRIPTION

The term "heteropolysaccharide" as used in the present invention isdefined as a water-soluble polysaccharide containing two or more kindsof sugar units, the heteropolysaccharide having a branched or helicalconfiguration, and having excellent water-wicking properties and immensethickening properties. When admixed with an appropriatehomopolysaccharide gum capable of cross-linking with theheteropolysaccharide in accordance with the present invention andexposed to an aqueous solution, gastric fluid, and the like, the gumspack closely and many intermolecular attachments are formed which makethe structure strong and provide a hydrophilic gum matrix having highgel strength.

Xanthan gum, the preferred heteropolysaccharide, is produced bymicroorganisms, for instance, by fermentation with the organismXanthomonas compestris. Most preferred is xanthan gum which is a highmolecular weight (>10⁶) heteropolysaccharide. Xanthan gum containsD-glucose, D-mannose, D-glucuronate in the molar ratio of 2.8:2.0:20,and is partially acetylated with about 4.7% acetyl. Xanthan gum alsoincludes about 3% pyruvate, which is attached to a single unitD-glucopyronosyl side chain as a metal It dissolves in hot or cold waterand the viscosity of aqueous solutions of xanthan gum is only slightlyaffected by changes in the pH of a solution between 1 and 11.

Other preferred heteropolysaccharides include derivatives of xanthangum, such as deacylated xanthan gum, the carboxymethyl ether, and thepropylene glycol ester.

The homopolysaccharide gums used in the present invention which arecapable of cross-linking with the heteropolysaccharide include thegalactomannans, i.e., polysaccharides which are composed solely ofmannose and galactose.

A possible mechanism for the interaction between the galactomannan andthe heteropolysaccharide involves the interaction between the helicalregions of the heteropolysaccharide and the unsubstituted mannoseregions of the galactomannan. Galactomannans which have higherproportions of unsubstituted mannose regions have been found to achievemore interaction with the heteropolysaccharide. Hence, locust bean gum,which has a higher ratio of mannose to the galactose, is especiallypreferred as compared to other galactomannans such as guar andhydroxypropyl guar.

The inert filler of the excipient preferably comprises apharmaceutically acceptable saccharide, including a monosaccharide, adisaccharide, and/or mixtures thereof. Examples of suitable inertpharmaceutical fillers include sucrose, dextrose, lactose,microcrystalline cellulose, fructose, xylitol, sorbitol, mixturesthereof and the like. However, it is preferred that a solublepharmaceutical filler such as lactose, dextrose, sucrose, or mixturesthereof be used.

The excipient of the present invention has uniform packingcharacteristics over a range of different particle size distributionsand is capable of processing into tablets using either directcompression, following addition of drug and lubricant powder orconventional wet granulation.

The properties and characteristics of a specific excipient systemprepared according to the present invention is dependent in part on theindividual characteristics of the homo and hetero polysaccharideconstituents, in terms of polymer solubility, glass transitiontemperatures and the like, as well as on the synergism both betweendifferent homo and heteropolysaccharides and between the homo andheteropolysaccharides and the inert saccharide constituent(s) inmodifying dissolution fluid-excipient interactions.

A homodisperse system of a heteropolysaccharide typically produces ahighly ordered, helical or double helical molecular conformation whichprovides high viscosity without gel formation. In contrast, ahomodisperse system of a homopolysaccharide typically is only slowlysoluble and ungelled at low temperatures. Two steps which are generallyrequired for gelation are the fast hydration of the macromolecules whichcomprise the hydrodisperse polysaccharide material and thereafter theassociation of the molecules to form gels. These two importantproperties which are necessary to achieve a slow release hydrophilicmatrix are maximized in the present invention by the particularcombination of materials. Prolonged exposure to the dissolution fluidpromotes solubilization, which allows molecules to associate and undergogelation, and may result in intermacromolecular cross-linking in ribbonor helical "smooth" regions.

The heterodisperse excipient of the present invention comprises bothhetero- and homo-polysaccharides which exhibit synergism. Theheteropolysaccharide component acts to produce a faster gelation of thehomopolysaccharide component and the homopolysaccharide acts tocross-link the normally free heteropolysaccharide helices. The resultantgel is faster-forming and more rigid. Heteropolysaccharides such asxanthan gum have excellent water wicking properties which provide fasthydration. On the other hand, the combination of xanthan gum withhomopolysaccharide gums which are capable of cross-linking the rigidhelical ordered structure of the xanthan gum (i.e. with unsubstitutedmannose regions in the galactomannans) thereby act synergistically toprovide a higher than expected viscosity (i.e., high gel strength) ofthe matrix. The combination of xanthan gum with locust bean gum with orwithout the other homopolysaccharide gums is especially preferred.However, the combination of any homopolysaccharide gums known to producea synergistic effect when exposed to aqueous solutions may be used inaccordance with the present invention. By synergistic effect, it ismeant that the combination of two or more polysaccharide gums produce ahigher viscosity and/or faster hydration than that which would beexpected by either of the gums alone.

It is also possible that the type of synergism which is present withregard to the gum combination of the present invention could also occurbetween two homogeneous or two heteropolysaccharides.

In the present invention, it has been discovered that the controlledrelease properties of the tablets are optimized when the ratio ofheteropolysaccharide gum to homopolysaccharide material is about 1:1,although heteropolysaccharide gum in an amount of from about 20 to about80 percent or more by weight of the heterodisperse polysaccharidematerial provides an acceptable slow release product.

The mixed individual and synergistic viscosity modifying and gel-formingcharacteristics of the excipient system of the present invention producea variety of possible release-controlling mechanisms in any givenexcipient system. Some of this behavior has been described by anequation such as that reported for example by Frisch, "Sorption andTransport in Glassy Polymers--A Review", Polymer Eng. Sci. 20 (1980),pp. 2-13, Fan & Singh, "Controlled Release: A Quantitative Treatment",published by Springer Verlag Berlin and London (1989), pp; 111-156; andKorsmeyer et al., "Mechanisms of Solute Release from Porous HydrophilicPolymers", Int. H. Pharm. 15 (1983), pp. 25-35:

    Mt/M∞=kt.sup.n

Where:

Mt/M∞ is the fractional solvent absorbed or drug released; t is thesolvent absorption or drug release time; k and n are kinetic constantswhich depend on and can be used to characterize the mechanism of solventsorption or drug release.

The mechanisms of solvent sorption and drug release vary from Case I orFickian diffusion (n=0.5, k=diffusion coefficient in initial half ofsolvent sorption (drug release); to Case II (n=1.0, k∝constant velocityof gel-glassy polymer interface); Super Case II (n>1 probably withFickian tailing ahead of slow Case II interface velocity) causingaccelerated solvent sorption and drug release when the solvent frontsmeet at a three dimensional centroid; and Anomalous Behavior (0.5<n<1),k is a characteristic of solvent/drug solution diffusion and polymerrelaxation.

In some cases, modulated drug release profiles are not well fitted tothis model and require a more complex function, which takes into accounta specific time at which the mechanism changes from one type to another,as the result of a time-dependent trigger for an excipient/excipient,excipient/fluid, drug/fluid, excipient/drug or mixed interaction. Thismay take the form of a power series such as:

    Mt/M∞=k.sub.1 t.sub.1 .sup.n1 +k.sub.2 t.sub.2.sup.n2

Alternatively, one skilled in the art will recognize that some otherfunction may more accurately model this complex behavior.

The rate-limiting step for the dissolution of tablets of the presentinvention is believed to be dependent to a large extent upon thepenetration of water (or gastric fluid) into the tablet to dissolve thepolysaccharides and the drug(s). It is further believed that thepresence of the surfactant in the formulation allows faster initialpenetration of fluid and an initial "burst" of drug release from theformulation. A second burst of drug release may then occur due to thefurther action of the surfactant, as the fluid front from one side ofthe tablet meets the fluid front on the opposite side. The abovehypotheses are included for discussion purposes only and are notintended to limit the scope of the present invention.

The chemistry of certain of the ingredients comprising the excipients ofthe present invention such as xanthan gum is such that the excipientsare considered to be self-buffering agents which are substantiallyinsensitive to the solubility of the medicament and likewise insensitiveto the pH changes along the length of the gastrointestinal tract.

The final formulation of the present invention comprises a sufficientamount of surfactant or wetting agent to provide a multi-phasic releaseof the drug(s). In certain preferred embodiments, the surfactant orwetting agent comprises from about 1 to about 10% of the finalformulation, by weight. However, the upper limit of the amount ofsurfactant or wetting agent included in the formulations of the presentinvention may be higher than 10%; the limiting concern being that thefinal product should provide a pharmaceutically acceptable formulation.For example, in the case of tablets, the upper limit of the amount ofsurfactant or wetting agent included is determined by the production ofa pharmaceutically acceptable tablet, e.g., a tablet which has afriability of less than about 1% and a hardness of 6-8 kg.

The surfactants which may be used in the present invention generallyinclude pharmaceutically acceptable anionic surfactants, cationicsurfactants, amphoteric (amphipathic/amphophilic) surfactants, andnon-ionic surfactants.

Suitable pharmaceutically acceptable anionic surfactants include, forexample, monovalent alkyl carboxylates, acyl lactylates, alkyl ethercarboxylates, N-acyl sarcosinates, polyvalent alkyl carbonates, N-acylglutamates, fatty acid-polypeptide condensates, sulfuric acid esters,alkyl sulfates (including sodium lauryl sulfate (SLS)), ethoxylatedalkyl sulfates, ester linked sulfonates (including docusate sodium ordioctyl sodium succinate (DSS)), alpha olefin sulfonates, and phosphatedethoxylated alcohols.

Suitable pharmaceutically acceptable cationic surfactants include, forexample, monoalkyl quaternary ammonium salts, dialkyl quaternaryammonium compounds, amidoamines, and aminimides.

Suitable pharmaceutically acceptable amphoteric(amphipathic/amphophilic) surfactants, include, for example,N-substituted alkyl amides, N-alkyl betaines, sulfobetaines, and N-alkylβ-aminoproprionates.

Suitable pharmaceutically acceptable wetting (solubilizing) agents,include pharmaceutically acceptable non-ionic surfactants such as, forexample, polyoxyethylene compounds, ethoxylated alcohols, ethoxylatedesters, ethoxylated amides, polyoxypropylene compounds, propoxylatedalcohols, ethoxylated/propoxylated block polymers, and propoxylatedesters, alkanolamides, amine oxides, fatty acid esters of polyhydricalcohols, ethylene glycol esters, diethylene glycol esters, propyleneglycol esters, glyceryl esters, polyglyceryl fatty acid esters, sorbitanesters, sucrose esters, and glucose (dextrose) esters.

Other suitable pharmaceutically acceptable wetting (solubilizing) agentsinclude acacia, benzalkonium chloride, cholesterol, emulsifying wax,docusate sodium, glyceryl monostearate, lanolin alcohols, lecithin,poloxamer, poloxyethylene castor oil derivatives, poloxyethylenesorbitan fatty acid esters, poloxyethylene stearates, sodium laurylsulfates, sorbitan esters, stearic acid, and triethanolamine.

Mixed surfactant/wetting agent systems are also useful in conjunctionwith the present invention. Examples of such mixed systems include, forexample, sodium lauryl sulfate/polyethylene glycol (PEG) 6000 and sodiumlauryl sulfate/PEG 6000/stearic acid.

The change in the mechanism of drug release from the excipients of thepresent invention from mono-phasic to bi- or multi-phasic release mayfurther be altered or enhanced by process changes during the manufactureof the excipient, or by formulation alteration. Further modifications inbi- or multi-phasic release profiles can be effected by addition ofsynergism-modifying components. For example, this can occur as a resultof selection of interacting polysaccharides in which the synergism ispotentiated by ionic strength of pH. In addition, the saccharidecomponent may also be changed, although the effect of differentsaccharides on drug release is much smaller than that of differentpolysaccharides, but may still be important in achieving fine control ofdrug release. The dissolution profiles of a tablet formulationcontaining an excipient system with a given heterodispersepolysaccharide component can also be modified by alteration of theratios of heteropolysaccharide to homopolysaccharide. Alternatively oradditionally, the drug release profiles can also be controlled bychanging the ratio of heterodisperse polysaccharides to saccharides inthe excipient system.

Delays in the onset of mono or multi-phasic release, which may bedesirable in order to optimize colonic absorption, can be producedthrough changes in core formulation or by application of tablet coatingsto further modify drug release patterns.

In addition to the inclusion of surfactants/wetting agents, the drugrelease mechanism of the controlled release excipient of the presentinvention may be further manipulated by altering the process utilizedfor tableting i.e. direct compression versus wet granulation versuscombination of both, and via changes in the formulation itself (i.e.,changes in the ratio of heterodisperse polysaccharide to insertsaccharide, and the like).

An effective amount of any generally accepted pharmaceutical lubricant,including the calcium or magnesium soaps may be added to theabove-mentioned ingredients of the excipient be added at the time themedicament is added, or in any event prior to compression into a saiddosage form. Most preferred is magnesium stearate in any amount of about0.5-3% by weight of the solid dosage form.

The combination of the heterodisperse polysaccharide material (i.e., amixture of xanthan gum and locust bean gum) with the inert saccharidediluent provides a ready-to-use product. A formulator need only blendthe desired active medicament and an optional lubricant with theexcipient and then compress the mixture to form slow release tablets.The excipient may comprise a physical admix of the gums along with asoluble excipient such as compressible sucrose, lactose or dextrose,although it is preferred to granulate or agglomerate the gums with plain(i.e., crystalline) sucrose, lactose, dextrose, and the like, to form anexcipient. The granulate form has certain advantages including the factthat it can be optimized for flow and compressibility; it can betableted, formulated in a capsule, extruded and spheronized with anactive medicament to form pellets, and the like.

The pharmaceutical excipients prepared in accordance with the presentinvention may be prepared according to any agglomeration technique toyield an acceptable excipient product.

In wet granulation techniques, the desired amounts of theheteropolysaccharide gum, the homopolysaccharide gum, and the inertsaccharide diluent are mixed together and thereafter a moistening agentsuch as water, propylene glycol, glycerol, alcohol or the like is addedto prepare a moistened mass. Next, the moistened mass is dried. Thedried mass is then milled with conventional equipment into granules.Therefore, the excipient product is ready to use.

The excipient is free-flowing and directly compressible. Accordingly,the excipient may be mixed in the desired proportion with atherapeutically active medicament and optional lubricant (drygranulation). Alternatively, all or part of the excipient may besubjected to a wet granulation with the active ingredient and thereaftertableted. The complete mixture, in an amount sufficient to make auniform batch of tablets, is then subjected to tableting in aconventional production scale tableting machine at normal compressionpressure, i.e. about 2000-1600 lbs/sq in. However, the mixture shouldnot be compressed to such a degree that there is subsequent difficultyin its hydration when exposed to gastric fluid.

One of the limitations of direct compression as a method of tabletmanufacture is the size of the tablet. If the amount of active is high apharmaceutical formulator may choose to wet granulate the active withother excipients to attain a decent size tablet with the right compactstrength. Usually the amount of filler/binder or excipients needed inwet granulation is less than that in direct compression since theprocess of wet granulation contributes to some extent toward the desiredphysical properties of a tablet.

The average tablet size for round tablets is preferably about 500 mg to750 mg and for capsule-shaped tablets about 750 mg to 1000 mg.

The average particle size of the granulated excipient of the presentinvention ranges from about 50 microns to about 400 microns andpreferably from about 185 microns to about 265 microns. The particlesize of the granulation is not narrowly critical, the importantparameter being that the average particle size of the granules mustpermit the formation of a directly compressible excipient which formspharmaceutically acceptable tablets. The desired tap and bulk densitiesof the granulation of the present invention are normally between fromabout 0.3 to about 0.8 g/ml, with an average density of from about 0.5to about 0.7 g/ml. For best results, the tablets formed from thegranulations of the present invention are from about 6 to about 8 kghardness. The average flow of the granulations prepared in accordancewith the present invention are from about 25 to about 40 g/sec. Tabletscompacted using an instrumented rotary tablet machine have been found topossess strength profiles which are largely independent of the inertsaccharide component. Scanning electron photomicrographs of largelytablet surfaces have provided qualitative evidence of extensive plasticdeformation on compaction, both at the tablet surface and across thefracture surface, and also show evidence of surface pores through whichinitial solvent ingress and solution egress may occur.

A wide variety of therapeutically active agents can be used inconjunction with the present invention. The therapeutically activeagents (e.g. pharmaceutical agents) which may be used in thecompositions of the present invention include both water soluble andwater insoluble drugs. Examples of such therapeutically active agentsinclude antihistamines (e.g., dimenhydrinate, diphenhydramine,chlorpheniramine and dexchlorpheniramine maleate), analgesics (e.g.,aspirin, codeine, morphine, dihydromorphone, oxycodone, and the like),anti-inflammatory agents (e.g., naproxyn, diclofenac, indomethacin,ibuprofen, acetaminophen, aspirin, sulindac), gastro-intestinals andanti-emetics (e.g., metoclopramide), anti-epileptics (e.g., phenytoin,meprobamate and nitrezepam), vasodilators (e.g., nifedipine, papaverine,diltiazem and nicardipine), anti-tussive agents and expectorants (e.g.,codeine phosphate), anti-asthmatics (e.g. theophylline), anti-spasmodics(e.g. atropine, scopolamine), hormones (e.g., insulin, heparin),diuretics (e.g., eltacrymic acid, bendrofluazide), anti-hypotensives(e.g., propranolol, clonidine), bronchodilators (e.g., albuterol),anti-inflammatory steroids (e.g., hydrocortisone, triamcinolone,prednisone), antibiotics (e.g., tetracycline), antihemorrhoidals,hypnotics, psychotropics, antidiarrheals, mucolytics, sedatives,decongestants, laxatives, antacids, vitamins, stimulants (includingappetite suppressants such as phenylpropanolamine). The above list isnot meant to be exclusive.

The ratio of medicament to the heterodisperse polysaccharide is based inpart upon the relatively solubility of the medicament and the desiredrate of release.

A computer aided pharmacokinetic model can be used to predict likely invivo drug blood levels from condition-independent in vitro drugprofiles.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The following examples illustrate various aspects of the presentinvention. They are not to be construed to limit the claims in anymanner whatsoever.

EXAMPLE 1

(Prior Art)

Tablets containing appropriate amounts of propranolol hydrochloridetogether with a homodisperse polysaccharide (locust bean gum) and aheterodisperse polysaccharide controlled release excipient (xanthangum/locust bean gum in a 1:1 ratio), inert pharmaceutical diluent(saccharide component), and 1% magnesium stearate are prepared eitherusing direct compression or following wet granulation in a high speedmixer processor (Baker Perkins Ltd., Stoke on Trent, U.K.), as describedin U.S. Pat. Nos. 4,994,276, 5,128,143 and 5,135,757. Tablets arecompacted to approximately 14 kP crushing force and in vitro testing iscarried out using an automated dissolution apparatus and the U.S.P.paddle method with a stirring speed of 50 rev min-¹. All of thedissolution studies are carried out in distilled water.

In vitro release profiles for propranolol hydrochloride tablets arefound to have first order profiles using a homodisperse polysaccharidewhereas a heterodisperse polysaccharide excipient provides a zero orderrelease profile. It is believed that this resulted from a synergisticinteraction between the homo- and heteropolysaccharides which occursthrough cross linking of the polymer chains and alters some of thephysical characteristics of the excipient, such as rate of glass-geltransition, polymer solubility, gel viscosity, rate of gelation and gelstrength. Variation of the heterodisperse polysaccharide/saccharidecomponent can also be used to modify drug release profiles further.Similar results are obtained when tablets are made usingchlorpheniramine maleate and verapamil hydrochloride as thetherapeutically active agents.

EXAMPLE 2

Prior Art

A slow release excipient is prepared by combining xanthan gum, locustbean gum, and dextrose in the amounts set forth in Table 1 below, anddry blending (Baker Perkin [Machine #5407], blender settings (chopper=1000 rpm, impeller =800 rpm)) the mixture for 2 minutes.

                  TABLE 1                                                         ______________________________________                                        Excipient Granulation                                                         Ingredient    %              g/1000 g                                         ______________________________________                                        Xanthan gum   25.0           225.0                                            Locust bean gum                                                                             25.0           225.0                                            Dextrose      50.0           450.0                                            Total         100.0%         900 g                                            ______________________________________                                    

Thereafter, water (115 ml) is added slowly and the mixture is blendedfor 1.5 minutes. The mixture is then dried overnight at 50° C. in anoven. Next, the mixture is screened through a 20 mesh screen, withparticles larger than 20 mesh being discarded.

In Example 2, 354.5 grams of the granulated slow release excipient and35.5 grams of phenylpropanolamine HCl are added into a 2 quart V-blenderand blended for 10 minutes. Next, 8 grams of Lubritab™ is added, and themixture is blended for 5 minutes. Thereafter, 2.0 grams of magnesiumstearate is added and the mixture is blended for 5 minutes. Finally, themixture is tableted to provide tablets of approximately 846 mg andapproximately 5-7 Kp. Further information concerning Example 2 is setforth in Table 2 below:

                  TABLE 2                                                         ______________________________________                                        Example 2                                                                     Ingredient     mg/tablet  %        g/400 g                                    ______________________________________                                        Excipient      750.0       88.6    354.5                                      Phenylpropanolamine                                                                           75.0       8.9      35.5                                      Lubritab ™   17.0       2.0      8.0                                       Magnesium stearate                                                                            4.0        0.5      2.0                                       Total          846 mg/tab 100%     400 g                                      ______________________________________                                    

EXAMPLES 3-10

In Example 3, the slow release granulation is prepared in similarfashion to Example 2, except that after the gums and dextrose arecombined, 130 ml of water is added, and the mixture is dried in anaromatic fluid bed dryer for 45 minutes at 70° C. (Type Strea-1). Theingredients of the slow release granulation of Example 3 are set forthin Table 3 below:

                  TABLE 3                                                         ______________________________________                                        Excipient Granulation                                                         Ingredient    %              g/1000 g                                         ______________________________________                                        Xanthan gum   25.0            250.0                                           Locust bean gum                                                                             25.0            250.0                                           Dextrose      50.0            500.0                                           Total         100.0%         1000 g                                           ______________________________________                                    

Thereafter, 336.4 grams of the granulated slow release excipient and33.6 grams of phenylpropanolamine HCl are added into a 2 quart V-blenderand blended for 10 minutes. Next, 20.0 grams of surfactant (sodiumlauryl sulfate) and 8 grams of Lubritab™ are added, and the mixture isblended for 5 minutes. Thereafter, 2.0 grams of magnesium stearate isadded and the mixture is blended for 5 minutes. Finally, the mixture istableted to provide tablets of approximately 892 mg and approximately5-7 Kp. Further information concerning Example 3 is set forth in Table 4below:

                  TABLE 4                                                         ______________________________________                                        Example 3                                                                     Ingredient     mg/tablet %         g/400 g                                    ______________________________________                                        Excipient      750/0     84.1      336.4                                      Phenylpropanolamine                                                                           75.0     8.4        33.6                                      *Surfactant (SLS)                                                                             44.7     5.0        20.0                                      Lubritab ™   17.8     2.0        8.0                                       Magnesium stearate                                                                            4.5      0.5        2.0                                       Total          892 mg/tab                                                                              100.0%    400 g                                      ______________________________________                                    

Examples 4-10 are prepared in similar fashion to Example 3. In each ofExamples 4-10, the formulations are dry blended with a 1:5 drug:gumratio. The percent of gum in the xanthan gum/locust bean gum/dextrosemixture in each formulation is 50%. Each formulation contains 75 mgphenylpropanolamine HCl and 750 mg of the slow release excipientgranulation, and this mixture is blended in a 2 quart v-blender for 10minutes. Then, 2% Lubritab™ is added along with the surfactant, andblended for 5 minutes. The surfactant used is sodium lauryl sulfateand/or docusate sodium. Finally, 0.5% of magnesium stearate is added andthe mixture is blended for 5 minutes, and tableted to the specifiedtablet weight. The tablet weights, amount (percentage) and type ofsurfactants used in Examples 3-10 are set forth in Table 5 below:

                  TABLE 5                                                         ______________________________________                                                              Granulation                                                                              Tablet wt.                                   Example   Surfactant* % Surfactant                                                                             (mg)                                         ______________________________________                                        Ex. 3     SLS         2          863.9                                        Ex. 4     SLS         5          891.9                                        Ex. 5     SLS         10         942.9                                        Ex. 6     DSS         2          863.9                                        Ex. 7     DSS         5          891.9                                        Ex. 8     DSS         10         942.9                                        Ex. 9     SLS + DSS   1 + 1      863.9                                        Ex. 10    SLS + DSS   2 + 2      882.4                                        ______________________________________                                         *SLS refers to sodium lauryl sulfate, and DSS refers to docusate sodium. 

EXAMPLES 11-12 DISSOLUTION TESTS--PERCENT DISSOLVED OVER TIME ANDRELEASE RATE

Next, dissolution studies are conducted for the tablets of Examples 2-10in order to determine the percent dissolved of drug over time, as wellas the release rate of the drug (phenylpropanolamine HCl). Thedissolution tests were conducted in a DI (deionized) water medium havinga volume of 1000 mL by the paddle method. The mixer rotation is 100 rpm,the height is 2.5 cm, the temperature is 37° C., and the wavelength usedis 210 nm. The calibration factor is determined according to thefollowing equation: ##EQU1##

The percent of the drug dissolved is then determined according to thefollowing equation:

    % active dissolved=calibration factor * absorbance of sample

The dissolution and release rate data for Examples 2-10 is based on a 6tablet dissolution study. The dissolution results expressed as percentdissolved are set forth in Tables 6-8 below:

                  TABLE 6                                                         ______________________________________                                        Examples 2-5                                                                  Percent Dissolved *(phenylpropanolamine HCl)*                                 Time     Ex. 2   Ex. 3      Ex. 4  Ex. 5                                      (hours)  no SLS  2% SLS     5% SLS 10% SLS                                    ______________________________________                                         1       22.0%   20.8%      15.3%  7.0%                                        2       34.4    33.2       23.6   11.7                                        3       42.5    41.6       29.6   15.4                                        4       49.6    48.5       34.9   19.2                                        5       56.0    54.6       40.4   24.8                                        6       62.9    62.8       48.2   31.6                                        7       69.5    73.0       69.6   39.6                                        8       74.6    87.9       77.9   52.2                                        9       78.1    91.2       82.2   55.1                                       10       80.7    95.9       85.2   56.7                                       11       83.6    96.0       88.6   58.8                                       12       87.8    98.0       91.1   60.1                                       13       90.6    98.0       94.1   61.6                                       14       94.2    99.6       96.8   67.0                                       15       98.7    100.0      98.9   73.5                                       16       100.0   --         100.0  79.7                                       17       --      --         --     83.1                                       18       --      --         --     90.0                                       19       --      --         --     96.0                                       20       --      --         --     100.0                                      ______________________________________                                    

                  TABLE 7                                                         ______________________________________                                        Examples 2 and 6-8                                                            Percent Dissolved *(phenylpropanolamine HCl)*                                 Time    Ex. 2    Ex. 6      Ex. 7  Ex. 8                                      (hours) no DSS   2% DSS     5% DSS 10% DSS                                    ______________________________________                                         1      22.0     17.7       15.4   15.2                                        2      34.4     27.1       23.3   22.8                                        3      42.5     33.9       29.1   28.4                                        4      49.6     39.4       34.0   33.4                                        5      56.0     44.6       38.9   40.7                                        6      62.9     52.0       46.2   55.4                                        7      69.5     64.8       59.2   65.4                                        8      74.6     66.0       66.3   67.6                                        9      78.1     70.9       69.7   69.3                                       10      80.7     75.2       71.6   70.3                                       11      83.6     78.5       75.2   75.7                                       12      87.8     87.0       77.1   78.6                                       13      90.6     94.3       79.8   79.3                                       14      94.2     94.3       84.0   82.2                                       15      98.7     98.5       88.1   86.9                                       16      100.0    100.0      93.5   89.5                                       17      --       --         92.8   90.9                                       18      --       --         95.4   93.2                                       19      --       --         97.4   94.2                                       20      --       --         99.4   96.1                                       21      --       --         100.0  97.2                                       22      --       --         --     98.5                                       23      --       --         --     99.3                                       24      --       --         --     100.0                                      ______________________________________                                    

                  TABLE 8                                                         ______________________________________                                        Examples 2 and 9-10                                                           Percent Dissolved *(phenylpropanolamine HCl)*                                                                    Ex. 10                                     Time   Ex. 2       Ex. 9           2% SLS +                                   (hours)                                                                              no SLS + DSS                                                                              1% SLS + 1% DSS 2% DSS                                     ______________________________________                                         1     22.0        15.5            16.5                                        2     34.4        22.6            26.5                                        3     42.5        28.2            33.5                                        4     49.6        32.8            38.0                                        5     56.0        36.9            46.4                                        6     62.9        40.7            54.8                                        7     69.5        45.0            61.5                                        8     74.6        51.4            67.7                                        9     78.1        56.9            68.6                                       10     80.7        61.0            73.5                                       11     83.6        64.2            78.9                                       12     87.8        68.7            83.2                                       13     90.6        73.8            85.2                                       14     94.2        77.3            87.0                                       15     98.7        78.4            90.2                                       16     100.0       85.4            94.0                                       17     --          88.3            97.5                                       18     --          93.0            99.3                                       19     --          96.1            100.0                                      20     --          98.5            --                                         21     --          99.1            --                                         22     --          100.0           --                                         ______________________________________                                    

FIGS. 1-9 are graphical representations of the dissolution curves(expressed as percent dissolved over time) provided by the tablets ofExample 2 (no surfactant added) and Examples 3-10 (surfactant(s)included), respectively. The dissolution results for Examples 2-10 areexpressed as release rates (expressed as mg/hr) are set forth in Tables9-11 below:

                  TABLE 9                                                         ______________________________________                                        Examples 2-5                                                                  Release Rate (mg/hr) *(phenylpropanolamine HCl)*                              Time     Ex. 2   Ex. 3      Ex. 4  Ex. 5                                      (hours)  no SLS  2% SLS     5% SLS 10% SLS                                    ______________________________________                                         1       22.0    20.8       15.3   7.0                                         2       12.4    12.4       8.30   4.70                                        3       8.10    8.40       6.00   3.7                                         4       7.10    6.90       5.30   3.80                                        5       6.40    6.10       5.50   5.60                                        6       6.90    8.20       7.80   6.80                                        7       6.60    10.2       21.4   8.00                                        8       5.10    14.9       8.30   12.6                                        9       3.50    3.30       4.30   2.90                                       10       2.60    4.70       3.00   1.60                                       11       2.90    0.10       3.40   2.10                                       12       4.20    2.00       2.50   1.30                                       13       2.80    0.00       3.00   1.50                                       14       3.60    1.60       2.70   5.40                                       15       4.70    0.40       2.10   6.50                                       16       1.30    0.00       1.10   6.20                                       17       0.00    --         0.00   3.40                                       18       --      --         --     6.90                                       19       --      --         --     6.00                                       20       --      --         --     4.00                                       21       --      --         --     0.00                                       ______________________________________                                    

                  TABLE 10                                                        ______________________________________                                        Examples 2 and 6-8                                                            Release Rate (mg/hr) *(phenylpropanolamine HCl)*                              Time    Ex. 2    Ex. 6      Ex. 7  Ex. 8                                      (hours) no DSS   2% DSS     5% DSS 10% DSS                                    ______________________________________                                         1      22.0     17.7       15.4   15.2                                        2      12.4     9.40       7.90   7.60                                        3      8.10     6.80       5.80   5.60                                        4      7.10     5.50       4.90   5.00                                        5      6.40     5.2        4.90   7.30                                        6      6.90     7.40       7.30   14.7                                        7      6.60     12.8       13.0   10.0                                        8      5.10     1.20       7.10   2.20                                        9      3.50     4.90       3.40   1.70                                       10      2.60     4.30       1.90   1.00                                       11      2.90     3.30       2.70   5.40                                       12      4.20     8.50       4.20   2.90                                       13      2.80     7.30       4.10   0.70                                       14      3.60     0.00       2.40   2.90                                       15      4.70     4.20       2.30   4.70                                       16      1.30     1.50       2.60   2.60                                       17      0.00     0.00       2.00   1.40                                       18      --       --         2.00   2.30                                       19      --       --         0.60   1.00                                       20      --       --         0.00   1.90                                       21      --       --         --     1.10                                       22      --       --         --     0.80                                       23      --       --         --     0.70                                       24      --       --         --     0.00                                       ______________________________________                                    

                  TABLE 11                                                        ______________________________________                                        Examples 2 and 9-10                                                           Release Rate *(phenylpropanolamine HCl)*                                                                         Ex.10                                      Time   Ex. 2       Ex. 9           2% SLS +                                   (hours)                                                                              no SLS + DSS                                                                              1% SLS + 1% DSS 2% DSS                                     ______________________________________                                         1     22.0        15.5            16.5                                        2     12.4        7.10            10.0                                        3     8.10        5.60            7.00                                        4     7.10        4.60            4.50                                        5     6.40        4.10            8.40                                        6     6.90        3.80            8.40                                        7     6.60        4.30            6.70                                        8     5.10        10.7            6.20                                        9     3.50        5.50            0.90                                       10     2.60        4.10            4.90                                       11     2.90        3.20            5.40                                       12     4.20        4.50            4.30                                       13     2.80        5.10            2.00                                       14     3.60        3.50            1.80                                       15     4.70        1.10            3.20                                       16     1.30        7.00            3.80                                       17     0.00        2.90            3.50                                       18     --          4.70            1.80                                       19     --          3.10            0.70                                       20     --          2.40            0.00                                       21     --          0.60            --                                         22     --          0.90            --                                         23     --          0.00            --                                         ______________________________________                                    

FIGS. 10-18 are graphical representations of the dissolution curves(expressed as release rate over time) provided by the tablets of Example2 (no surfactant added) and Examples 3-10 (surfactant(s) included). Asis readily apparent from the results, the formulations of Examples 3-10provide a multi-phasic release of phenylpropanolamine HCl.

The examples provided above are not meant to be exclusive. Many othervariations of the present invention would be obvious to those skilled inthe art, and are contemplated to be within the scope of the appendedclaims.

What is claimed is:
 1. A controlled-release oral solid dosage form forabsorption of an active medicament in the gastrointestinal tract,comprisingan effective amount of a medicament to render a therapeuticeffect; a controlled release excipient comprising a heterodisperse gummatrix comprising a heteropolysaccharide gum and a homopolysaccharidegum capable of cross-linking said heteropolysaccharide gum in thepresence of aqueous solutions, the ratio of said heteropolysaccharidegum to said homopolysaccharide gum being from about 1:3 to about 3:1;and an inert pharmaceutical diluent selected from the group consistingof a monosaccharide, a disaccharide, a polyhydric alcohol, and mixturesthereof, the ratio of said inert diluent to said heterodisperse gummatrix being from about 3:7 to about 7:3; and from about dosage 4 toabout 10 percent by weight of a multi-phasic release promoting agent toprovide a multi-phasic release of said medicament when said dosage formis exposed to aqueous fluids.
 2. The oral solid dosage form of claim 1,wherein said a heteropolysaccharide gum comprises xanthan gum and saidhomopolysaccharide gum comprises locust bean gum.
 3. The oral soliddosage form of claim 2, wherein said multi-phasic release promotingagent comprises about 4 to about 5 percent of said formulation, byweight.
 4. The oral solid dosage form of claim 1, which releases saidmedicament according to bi-phasic kinetics.
 5. The oral solid dosageform of claim 1, wherein the ratio of said inert diluent to saidheterodisperse gum matrix is about 1:1.
 6. The oral solid dosage form ofclaim 3, wherein said multi-phasic release promoting agent is selectedfrom the group consisting of pharmaceutically acceptable anionicsurfactants, cationic surfactants, amphoteric (amphipathic/amphophilic)surfactants, and mixtures of any of the foregoing.
 7. The oral soliddosage form of claim 3, wherein said multi-phasic release promotingagent is an anionic surfactant selected from the group consisting ofmonovalent alkyl carboxylates, acyl lactylates, alkyl ethercarboxylates, N-acyl sarcosinates, polyvalent alkyl carbonates, N-acylglutamates, fatty acid-polypeptide condensates, sulfuric acid esters,alkyl sulfates, ethoxylated alkyl sulfates, ester linked sulfonates,alpha olefin sulfonates, phosphated ethoxylated alcohols, and mixturesof any of the foregoing.
 8. The oral solid dosage form of claim 3,wherein said multi-phasic release promoting agent is a cationicsurfactant selected from the group consisting of monoalkyl quaternaryammonium salts, dialkyl quaternary ammonium compounds, amidoamines,aminimides, and mixtures of any of the foregoing.
 9. The oral soliddosage form of claim 3, wherein said multi-phasic release promotingagent is an amphoteric surfactant selected from the group consisting ofN-substituted alkyl amides, N-alkyl betaines, sulfobetaines, N-alkylβ-aminoproprionates, and mixtures of any of the foregoing.
 10. The oralsolid dosage form of claim 3, wherein said multi-phasic releasepromoting agent is a non-ionic surfactant selected from the groupconsisting of ethoxylated alcohols, ethoxylated esters, ethoxylatedamides, propoxylated alcohols, ethoxylated/propoxylated block polymers,propoxylated esters, alkanolamides, amine oxides, fatty acid esters ofpolyhydric alcohols, ethylene glycol esters, diethylene glycol esters,propylene glycol esters, glyceryl esters, sorbitan esters, sucroseesters, glucose (dextrose) esters, and mixtures of any of the foregoing.11. The oral solid dosage form of claim 3, wherein said multi-phasicrelease promoting agent is a wetting agent selected from the groupconsisting of acacia, benzalkonium chloride, cholesterol, emulsifyingwax, docusate sodium, glyceryl monostearate, lanolin alcohols, lecithin,poloxamer, poloxyethylene castor oil derivatives, poloxyethylenesorbitan fatty acid esters, poloxyethylene stearates, sodium laurylsulfates, sorbitan esters, stearic acid, triethanolamine, and mixturesof any of the foregoing.
 12. The oral solid dosage form of claim 3,wherein said multi-phasic release promoting agent is selected from thegroup consisting of sodium lauryl sulfate/polyethylene glycol (PEG) 6000and sodium lauryl sulfate/PEG 6000/stearic acid.
 13. The oral soliddosage form of claim 1, wherein said multi-phasic release promotingagent comprises sodium lauryl sulfate.
 14. The oral solid dosage form ofclaim 1, wherein said multi-phasic release promoting agent comprisesdocusate sodium.
 15. The oral solid dosage form of claim 1, wherein saidmulti-phasic release promoting agent comprises sodium lauryl sulfate anddocusate sodium.
 16. The oral solid dosage form of claim 1, wherein saidtherapeutically active medicament is selected from the group consistingof antihistamines, analgesics, gastro-intestinals, anti-emetics,anti-epileptics, vasodilators, anti-tussive agents, expectorants,anti-asthmatics, anti-spasmodics, hormones, diuretics,anti-hypotensives, anti-inflammatory steroids, antibiotics,antihemorrhoidals, hypnotics, psychotropics, antidiarrheals, mucolytics,sedatives, decongestants, laxatives, antacids, vitamins, and stimulants.17. The oral solid dosage form of claim 1, wherein said therapeuticallyactive medicament is phenylpropanolamine HCl.
 18. A controlled releasetablet for oral administration comprising(i) a heterodisperse gum matrixcomprising xanthan gum and locust bean gum in a ratio about 1:1; (ii) aninert pharmaceutically acceptable diluent selected from the groupconsisting of a monosaccharide, a disaccharide, and mixtures thereof,the ratio of said diluent to said heterodisperse gum matrix being fromabout 3:7 to about 7:3; (iii) an affective amount of a medicament torender a therapeutic effect; and (iv) from at least 2 to about 10percent by weight of a pharmaceutically acceptable multi-phasic releasepromoting agent selected from the group consisting of sodium laurylsulfate, docusate sodium, and mixtures thereof, said medicament having amulti-phasic release of said medicament when exposed to aqueous fluid.19. The dosage form of claim 18 which releases said medicament accordingto bi-phasic kinetics.
 20. The tablet of claim 18, wherein saidtherapeutically active medicament is selected from the group consistingof antihistamines, analgesics, gastro-intestinals, anti-emetics,anti-epileptics, vasodilators, anti-tussive agents, expectorants,anti-asthmatics, anti-spasmodics, hormones, diuretics,anti-hypotensives, anti-inflammatory steroids, antibiotics,antihemorrhoidals, hypnotics, psychotropics, antidiarrheals, mucolytics,sedatives, decongestants, laxatives, antacids, vitamins, and stimulants.21. The oral solid dosage form of claim 1 which comprises a tablet. 22.The oral solid dosage form of claim 16 which comprises a tablet.
 23. Theoral solid dosage form of claim 18 which comprises a tablet.
 24. Theoral solid dosage form of claim 20 which comprises a tablet.